Upregulation of T-type Ca2+ channels in long-term diabetes determines increased excitability of a specific type of capsaicin-insensitive DRG neurons.
Upregulation of T-type Ca2+ channels in long-term diabetes determines increased excitability of a specific type of capsaicin-insensitive DRG neurons.
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DOI：
10.1186/s12990-015-0028-z
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发表时间：
2015-05-20
期刊：
影响因子：
3.3
通讯作者：
Belan PV
中科院分区：
文献类型：
--
作者：
Duzhyy DE;Viatchenko-Karpinski VY;Khomula EV;Voitenko NV;Belan PV
先前的研究表明，在短期（2-4周）链脲佐菌素诱导的糖尿病大鼠中，辣椒素敏感性DRG神经元的兴奋性增加和热痛觉过敏是由T型Ca 2+电流上调介导的。在长期糖尿病（第8周后）热痛觉过敏改变为痛觉减退，伴随着辣椒素敏感的小尺寸伤害感受器中的T型电流的下调。同时，在糖尿病进展到后期阶段期间，STZ糖尿病动物和患者中除热以外的糖尿病神经病变的疼痛症状持续存在，这表明其他类型的DRG神经元可能被致敏并导致疼痛。在这项研究中，我们研究了辣椒素不敏感的DRG神经元和这些神经元的兴奋性在长期糖尿病大鼠和热痛觉减退的糖尿病大鼠的T型钙通道的功能表达。在这里，我们已经证明，在STZ糖尿病T型电流上调辣椒素不敏感的低pH敏感的小尺寸伤害性DRG神经元的长期糖尿病大鼠和热痛觉减退的糖尿病大鼠。这种上调并不伴随着T型通道的生物物理性质的显着变化，表明功能活性通道的密度增加。T型电流对阿米洛利（1 mM）和低浓度Ni 2+（50 μM）的敏感性表明Cav3.2亚型T型通道在未处理和糖尿病大鼠的辣椒素不敏感低pH敏感神经元中普遍存在。T-型通道的上调导致这些伤害性神经元的神经元兴奋性增加，表现为动作电位起始阈值降低、后去极化电位显著和爆发性放电。在长期糖尿病过程中，这些神经元的钠电流没有显著变化，并且不能促进糖尿病诱导的神经元兴奋性增加。辣椒素不敏感的低pH敏感型DRG神经元显示糖尿病诱导的Cav3.2亚型T型通道上调。这种上调导致这些神经元的兴奋性增加，并可能有助于晚期糖尿病的非热伤害感受。
Previous studies have shown that increased excitability of capsaicin-sensitive DRG neurons and thermal hyperalgesia in rats with short-term (2–4 weeks) streptozotocin-induced diabetes is mediated by upregulation of T-type Ca2+ current. In longer–term diabetes (after the 8th week) thermal hyperalgesia is changed to hypoalgesia that is accompanied by downregulation of T-type current in capsaicin-sensitive small-sized nociceptors. At the same time pain symptoms of diabetic neuropathy other than thermal persist in STZ-diabetic animals and patients during progression of diabetes into later stages suggesting that other types of DRG neurons may be sensitized and contribute to pain. In this study, we examined functional expression of T-type Ca2+ channels in capsaicin-insensitive DRG neurons and excitability of these neurons in longer-term diabetic rats and in thermally hypoalgesic diabetic rats. Here we have demonstrated that in STZ-diabetes T-type current was upregulated in capsaicin-insensitive low-pH-sensitive small-sized nociceptive DRG neurons of longer-term diabetic rats and thermally hypoalgesic diabetic rats. This upregulation was not accompanied by significant changes in biophysical properties of T-type channels suggesting that a density of functionally active channels was increased. Sensitivity of T-type current to amiloride (1 mM) and low concentration of Ni2+ (50 μM) implicates prevalence of Cav3.2 subtype of T-type channels in the capsaicin-insensitive low-pH-sensitive neurons of both naïve and diabetic rats. The upregulation of T-type channels resulted in the increased neuronal excitability of these nociceptive neurons revealed by a lower threshold for action potential initiation, prominent afterdepolarizing potentials and burst firing. Sodium current was not significantly changed in these neurons during long-term diabetes and could not contribute to the diabetes-induced increase of neuronal excitability. Capsaicin-insensitive low-pH-sensitive type of DRG neurons shows diabetes-induced upregulation of Cav3.2 subtype of T-type channels. This upregulation results in the increased excitability of these neurons and may contribute to nonthermal nociception at a later-stage diabetes.
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影响因子：
5.5
作者：
HU, GY;HVALBY, O;ANDERSEN, P
通讯作者：
ANDERSEN, P
影响因子：
8.2
作者：
Calcutt, NA;Freshwater, JD;Mizisin, AP
通讯作者：
Mizisin, AP
影响因子：
4.8
作者：
Hong, SS;Morrow, TJ;Wiley, JW
通讯作者：
Wiley, JW
DOI：
10.1007/978-1-60761-880-5_9
发表时间：
2011-01-01
期刊：
ANIMAL MODELS OF PAIN
影响因子：
--
作者：
Dobretsov, Maxim;Backonja, Miroslav (Misha);Stimers, Joseph R.
通讯作者：
Stimers, Joseph R.
影响因子：
5.3
作者：
Fang, Xin;Djouhri, Laiche;Lawson, Sally N.
通讯作者：
Lawson, Sally N.